Idiopathic pulmonary fibrosis is a diffuse interstitial lung disease of unknown etiology characterized by chronic inflammation and progressive fibrosis and carries a 3-year, 50% mortality. Currently, there are no effective treatments for IPF as it responds poorly to currently available therapy, which consists of corticosteroids and other immunosuppressive agents. Hence, there is a critical need to develop pharmacologic agents that delay or reverse pulmonary fibrosis. Accumulating evidence indicates that transforming growth factor-beta plays an important role in the pathogenesis of pulmonary fibrosis, and therefore TGF? antagonists may serve as important therapeutic target for pulmonary fibrosis. Our search for pathways that inhibit the actions of TGF? led us to the study of signal transduction by Vitamin D and its receptor (VDR). In this project we will test the hypothesis that the lung is a target organ for 1,25 dihydroxyvitamin D and that dysregulated Vitamin D metabolism and signaling in lung is associated with progressive IPF. The aims of this proposal are to: i) quantitate lung and systemic Vitamin D metabolites in IPF and control subjects ii) determine lung-specific expression and activation state of the Vitamin D receptor, and iii) characterize the expression and distribution of the Vitamin D 25-, 11-, and 24- hydroxylases in the lung. Collectively, these studies will provide important mechanistic insights into the regulation of lung homeostasis by Vitamin D signaling pathways. PUBLIC HEALTH RELEVANCE: In trying to determine a mechanism of disease, the goal of this project is to establish a link between vitamin D deficiency and pulmonary fibrosis. This research has broader implications for the treatment of scarring diseases of other organs. (End of Abstract)